The long-term objective of the proposal is to determine the mechanisms by which exposure to salient social defeat stress may augmenting behavioral response to a subsequent drug challenge, producing cross sensitization. In humans the response to social stress also can be maladaptive, resulting in the exacerbation of many psychiatric disorders. The current proposal investigates the mechanism by which stress-induced alteration of opioid activity in the ventral tegmental area (VTA) influences the mesocorticolimbic dopamine system. We hypothesize that activation of the VTA opioid system is an important initiating neuroadaptation, which alters mesolimbic dopamine neurotransmission following social defeat stress. The specific aims are (1) to study temporal patterns of, mu-opioid receptor mRNA expression and receptor binding in the VTA after repeated social defeat stress and also the localization of, mu-opioid expression in the VTA; (2) to estimate the functional significance of mu-opioid receptors in the VTA at different time points after repeated social defeat stress using behavioral and neurochemical measures; and (3) to determine the effects of repeated social defeat stress on subsequent psychostimulant response. By combining techniques, which allow characterization of in vivo responses (locomotion after opioid stimulation and psychostimulant challenge) and alterations in mRNA expression and binding of mu-opioid receptors, as well as dopamine release regions innervated by VTA dopamine neurons, we will be able to more fully characterize the consequences of repeated social defeat stress. Upregulation of VTA mu-opioid receptors as a consequence of exposure to social defeat stress provides a novel mechanism for modulation of mesolimbic dopaminergic activity, which can predispose an organism to a heightened response to abused drugs or subsequent stress (i.e., sensitization). The anticipated results will elucidate a potential mechanism of cross-sensitization following repeated social defeat stress, which is implicated in the development of enhanced vulnerability to drugs of abuse.